Autophagy (Greek, 'self-eating') is an evolutionarily conserved homeostatic process by which cytoplasmic components are sequestered into double-membraned vesicles (autophagosome) and delivered to lysosomes for degradation and recycling. This process has been increasingly recognized as essential for cell survival, differentiation, and development, and is often misregulated in human diseases, including cancer. While it has been speculated that autophagy may both benefit and hinder tumor development/progression, recent data indicates that autophagy principally serves as a tumor suppressor pathway. Yet, despite its importance, the mechanisms by which autophagy functions in tumor suppression remain largely undetermined. The proposed study is directed toward investigating how autophagy contributes to tumor suppression and how its defects contribute to malignancy, with a specific focus on a novel autophagic UVRAG gene that is monoallelically mutated at high frequencies in human cancers. Our preliminary studies have UIKO findings, we hypothesize that UVRAG is a novel autophagic tumor suppressor, which cooperates with Beclin1 and the HOPS complex to activate autophagy and inhibit tumor development. Genetic, biochemical and cell biological studies will primarily focus on defining in mechanistic detail the dual roles of UVRAG in autophagosome formation (Aim 1) and autophagosome maturation (Aim 2), and their functional significance in UVRAG tumor suppressor activity (Aim 3). Insights gained from this study will not only illuminate new views on the autophagy regulatory network, but also suggest new strategy for cancer control. PUBLIC HEALTH RELEVANCE: Many studies have shed light on the role of autophagy in cancer biology, making it an attractive therapeutic target, but it remains unclear and controversial whether autophagy suppresses tumorigenesis or favors tumor growth. The challenge of the proposed study is to investigate the molecular basis of autophagy in tumor development with a specific focus on a novel autophagic tumor suppressor UVRAG, which may ultimately contribute to the establishment of new therapeutic strategy for cancer control.